Prostaglandin synthase (PGHS) is the enzyme that mediates biosynthesis of prostaglandins (PGs) and thromboxane (TxA2) from arachidonic acid, and whose inhibition underlies the effectiveness of a variety of anti-inflammatory drugs (Sharma and Sharma, 1997, Indian J. Exp. Biol. 35: 1025-1031; Morteau, 2000, Arch. Immunol. Ther. Exp. 48: 473-480; Llorens, 2002, J. Mol. Graph Model. 20: 359-371; Smith et al., 2000, Annu. Rev. Biochem. 69: 145-182; FitzGerald and Patrono, 2001, N. Engl. J. Med. 345: 433-442; Vane and Botting, 1998, Inflamm. Res. 47: S78-S87). PGHS activity originates from two distinct and independently regulated isozymes, PGHS-1 and PGHS-2 (Dannhardt and Kiefer, 2001, Eur. J. Med. Chem. 36: 109-126; Otto and Smith, 1995, J. Lipid Mediat. Cell. Signal. 12: 139-156; Oberle et al., 1998, Circ. Res. 82: 1016-1020). PGHS-2 is the dominant source of PGs which mediate pain and inflammation, while PGHS-1 catalyzes the formation of PGs that subserve housekeeping functions, such as the maintenance of gastrointestinal (GI) integrity. Traditional non-steroidal anti-inflammatory drugs (NSAIDs) inhibit both PGHS-1 and PGHS-2. A consequence of PGHS-1 inhibition, however, has been adverse gastrointestinal effects, including both direct and indirect irritation of the gastrointestinal tract, on NSAID therapies.
The coxibs, selective inhibitors of PGHS-2, were designed to inhibit the major enzymatic source of the PGs which mediate pain and inflammation, while sparing PGHS-1-derived PGs, which contribute dominantly to gastric cytoprotection (FitzGerald and Patrono, 2001, N. Engl. J. Med. 345: 433-42). Two coxibs, rofecoxib (Bombardier et al., 2000, N. Engl. J. Med. 343:1520-8, 2 p following 8) and lumiracoxib (Schnitzer et al., 2004, Lancet 364:665-74) have been shown in controlled trials to reduce the incidence of serious gastrointestinal (GI) adverse effects when compared with traditional NSAIDs.
All of the coxibs depress substantially the level of prostacyclin (PGI2), leaving platelet COX-1-derived thromboxane A2 (TxA2) level unaffected (McAdam et al., 1999, Proc. Natl. Acad. Sci. USA 96: 272-7; Catella-Lawson et al., 1999, J. Pharmacol. Exp. Ther. 289; 735-41). PGI2, the dominant product of arachidonic acid in macrovascular endothelial cells, is formed by prostacyclin synthase (PGIS) action on prostaglandin endoperoxide intermediates, which are produced catalytically by PGHS-2 (Moncada et al., 1976, Nature 263: 663-5). PGI2 exhibits properties of potential relevance to atheroprotection. Specifically, it inhibits platelet aggregation, vascular smooth muscle contraction and proliferation (Cheng et al., 2002, Science 296: 539-541), leukocyte-endothelial cell interactions (Della Bella et al., 2001, Prostaglandins 65: 73-83) and cholesteryl ester hydrolase (Gryglewski et al., 1995, Ann. N.Y. Acad. Sci. 748: 194-206; discussion 206-7). It also activates reverse cholesterol transport (Morishita et al., 1990, J. Clin. Invest. 86: 1885-91). Indirect evidence suggests that PGI2 protects against oxidant-induced tissue injury. Deletion of the PGI2 receptor (IP) or suppression of PGI2 biosynthesis augments cardiac injury caused by ischemia/reperfusion (Xiao et al., 2001, Circulation 104: 2210-5) or the anthracycline, doxarubacin (Dowd et al., 2001, J. Clin. Invest. 108: 585-90).
PGI2 also limits the cardiovascular effects of thromboxane A2 (TxA2), the major PGHS-1 product of platelets (Cheng et al., 2002, Science 296: 539-541). The cardiovascular effects of TxA2 include: platelet aggregation (Thomas et al., 1998, J. Clin. Invest. 102:1994-2001), elevation of blood pressure (Qi et al., 2002, J. Clin. Invest. 110: 61-9; Francois et al., 2004, Hypertension 43:364-9) and acceleration of atherogenesis (Kobayashi et al., 2004, J. Clin. Invest. 114:784-94; Cayatte et al., 2000, Arterioscler. Thromb. Vasc. Biol. 20: 1724-8; Huo et al., 2003, Nat. Med. 9: 61-7).
Rofecoxib has been associated with an excess of heart attack and stroke in patients receiving this drug (25 mg/day) in the Adenomatous Polyp Prevention on VIOXX® (APPROVe) trial, and has recently been withdrawn from the market (FitzGerald, 2004, N. Engl. J. Med. 351:1709-11). A similar excess in cardiovascular events has recently been reported with celecoxib, again in a trial designed to prevent colonic adenomas (www(dot)nih(dot)gov/news/pr/dec2004/od-17(dot)htm). Furthermore, evidence has emerged to link a structurally distinct coxib, valdecoxib, to a cardiovascular hazard (Ott et al., 2003, J. Thorac. Cardiovasc. Surg. 125: 1481-92), suggesting strongly that this increased cardiovascular risk is a class effect for the coxibs. Indeed, valdecoxib has also been recently withdrawn from the market (www(dot)fda(dot)gov/bbs/topics/news/2005//NEW01171 (dot)html).
Due to their undesirable side effects, alternatives to NSAIDs and coxibs are being sought for treatment of inflammation and pain. In this regard, attention has turned to microsomal prostaglandin E synthase-1 (mPGES-1), a stimulus-inducible enzyme that functions downstream of PGHS-2 in the production of prostaglandin E2 (PGE2) (see, e.g., Jakobsson et al., 1999, Proc. Natl. Acad. Sci. USA 96:7220-7225). mPGES-1 enzyme colocalizes with both PGHS enzymes (Pini et al., 2005, Arterioscler. Thromb. Vasc. Biol. 25:315-20; Schneider et al., 2004, Kidney Int. 65:1205-13). PGE2 has been shown to be involved in arthritis and inflammation and thus, mPGES-1 has been suggested as a new drug target (see, e.g., Trebino et al., 2003, PNAS 100:9044-9049; Fahmi et al., 2004, Curr. Opin. Rheumatology 16:623-627; Kojima et al., 2005, Fundam. Clin. Pharmacol. 19:255-261).
To date, however, the cardiovascular profile of mPGES-1 and PGE2 has not been determined. Specifically, it is unknown whether selective inhibition of mPGE2 would avoid the undesirable cardiovascular consequences of PGHS-2 inhibtion. There is reason to think it might not. Suppression of PGE2 is thought to account for the hypertension the can accompany treatment with NSAIDs or coxibs. In addition, PGE2 affects platelet aggregation in variable, concentration dependent ways (Fabre et al., 2001, J. Clin. Invet. 107:603-610). In particular, at low concentration, PGE2 enhances platelet aggregation, suggesting depressing PGE2 levels by inhibitng mGPES-1 may have undesirable side effects, such as accelerating thrombogenesis.
There exists a need in the art for a treatment for inflammation and pain that does not cause an elevated cardiovascular risk. The present invention addresses and meets these needs.